Halosteroids and preparation of the same



Patented Oct. 10, 1944 UNITED STATES PATENT OFFICE HALOSTEROIDS ANDPREPARATION OF THE SAME Russell Earl Marker, State College, Pa.,and'Harry M. Crooks, Jr.,

Detroit, Mich., assignors to Parke, Davis & Company, Detroit, Mich-., acorporation of Michigan N Drawing.

1941, Serial N0. 409,590.

Original application September 4,

Divided and this application September 14, 1942, Serial No. 458,332

20 Claims. (Cl. 260-3914) The invention relates to the preparation ofsteroid compounds useful as intermediates in the preparation of certainhormones. V

The present application relates to the conversion of17,21-dihal0-20-keto steroids, first into A -21-halo-20-keto steroidsand then into 21- halo-20-keto steroids. The 21-ha1o-A -unsaturatedlZO-keto pregnane compounds are a new class of compounds particularlyuseful for the tpreparation of substancesof the cortical hormone ype.

This application is a division of our copending application, Serial No.409,590, filed September 4, 1941. In said copending application thepreparation of 17,21-dihalo steroids is described and claimed.

These compounds have in ring D the following formula where X is chlorineor bromine. Rings ;A B and C may be unsubstituted or may bearsubstituents such as OH, -O-acyl and Hal, and, furthermore, may have oneor more points of unsaturation such, for example, as a double bond at ARegardless of these particular features in rings A, B and -C, thetransformation in ring D proceeds according to the following diagram:

CHzX

dchydrohal ogenating agent reduct ion e. g. hydrogenati on with Pdcatalyst hydrollysis V Dehydrohalogenating agents suitable for the firststep in the above diagram include the combinationbf an organiccarboxylic-acid and an alkali metal salt of an organic carboxylic-acid,

. Example 1 I A. 17,21-dibromo preqnanolfi-(,6) o11.e-20 aceta ta-Asolution of -5 g. of pregnanol-3-(fi) -one- 2.0 acetate in cc. ofglacialacetic acid cont-aining 2 drops of 48% hydrobromic acid is warmedto 40 C. and then 29 cc. of 1 M. bromine in acetic acid is addeddropwise. After the solution has stood for fifteen minutes it is pouredinto water and the precipitated solid collected and washed with water.The solid is recrystallized trom acetone to givewhite crystalsof-17,21-dibromo-pregtassium acetate in 800 cc. of glacial acetic acidis refluxed for ninety minutes. Then the reaction mixture isconcentrated in vacuo to a volume of 100 cc., diluted with water and theprecipitated solid taken up in ether. The ethereal extract is washedwith 5% sodium bicarbonate solution and with water and then the ether isremoved on a steam bath. The residue is fractionally crystallized frommethanol. There is obtained first an appreciable amount of unreactedstartingmaterial, 17,2l-dibromo-pregnanol-Zi-(13) -one acetate, M. P.190-191 C. Further concentration of the mother liquors, however, yieldsthe desired product, 21 bromo A -pregnenol-3- (l8) -0ne-20 acetate, aswhite plates of M. P. 151-154 C.

Anal. Calcd, for C23H33O3Br2 C, 63.1; H, 7.6. Found: C, 63.3; H, 7.8.

C. zi-bromo-p r e g n a n o l-3-(p) -0'ne-20 acetate-A solution of 1 g.of 21-bromo-A -pregneno1-3-(;8)-one-2O acetate in 100 cc. of dioxane isshaken with 2 g. of palladium-barium sulfate catalyst and hydrogen at 3atmospheres pressure at room temperature for two hours. Then the mixtureis filtered and the filtrate concentrated in vacuo. The residue iscrystallized from methanol to give fine white needles of21-bromopregnanol-3-(fi) -0ne-2.0 acetate, M. P. 145-147 C.

D. Reaction of 21 -br0mo-preynanoZ-3-(B) -one- 20 acetate with1J0tasiuma0etate.-A solution of 0.8 g. of 21-bromo-pregnanol-3-(fi)-one-20 acetate and 1 g. of fused potassium acetate in 100 cc. ofglacial acetic acid is refluxed for three hours. Then the solution isconcentrated in vacuo and poured into water. The precipitated solid istaken up in ether, the ethereal extract washed well with water and thenthe ether is evaporated on a steam bath. The residue is crystallizedfrom methanol to give pregnanediol-3-(fl) ,21-one-20 diacetate of M. P.145-146 C.

Example 2 .ment with Norite and the ether evaporated on ether to givepregnanediol-3-(p), 2-1-one-20 21- i 300 cc. of glacial acetic acid at40 C. is added several drops, of 48% hydrobromic acid. Then 62.6 cc. of1 M. bromine in acetic acid is-added dropwise. Afterthe addition ofbromine is completed; the solution is poured into water and theprecipitated solid collected and washed with water. The solid iscrystallized from ether to give thick white needles of17,21-dibromo-pregnanol- 3-(13) -one-20 of M. P. 190-192". C.

On treatment with iron and acetic acid, 17,21 dibromo-pregnanol-3- (,8)=one-201 yields" pregnanol-3-(,l3)-one-20. 1

B. 21 -b 1' o m o-A -pregnenoZ 3-'-(s) -o'ne-20. -A solution of 2 g. of17,21-dibromo-pregnanol-3- (13) -one-20 and 2 g. of fused potassiumacetate 7 in 300 cc. of glacial'acetic acid is refluxed for two hours.The solution is concentrated in vacuo, diluted with water andthe-precipitated solid taken up in ether. The ethereal extract iswashedwell with water, the ether evaporated and the residue crystallized frommethanol to ive'21- br0m0-A -pregnenol-3-([3) -one-20 as white crystalsof M. P. 155-157 C. V 1' e C. 21 ,-bromo-pregnanoZ'-3-( 3) -one-2 0.-.-Asolution of 2 .g. of zl-bromo-A -pregnenol-lil3 one-2O in cc. of dioxaneis shaken with 4 g. 05 palladium barium sulfate catalyst and hydrogen at3 atmospheres pressure at room temperature for two hours. I Then themixture is filtered and the filtrate evaporated to dryness in vacuo. Theresidue is crystallized from methanol to give white crystals of21-bromo-pregnanol-3-(p)-one-20, M. P. 127-128 C.

D. Reaction of 21-bromo-pregnanoZ-3-(p)-one- 20 with potassiumacetate.-A mixture of 0.9 g. of 21-bromo-pregnanol-3-(p) -0ne-20, 3 g.of fused potassium acetate and 10 cc. of glacial acetic acid is refluxedfor three and. one-half hours. Then the reaction mixture is diluted withwater and the precipitated solid taken up in ether. The ethereal extractis washed with water, decolorized b treatthe steambath. The residue iscrystallized from monoacetate, M. P. 121-123 C. I

From the above examples it will be noted that this" invention isparticularly useful for converting a 17,21-dihalo-pregnano1-3 one-20 oran ester thereof into a 21-halo-pregnanol-3-one-20 or an ester thereofwhich in turn may be converted into 21-hydroxy pregnanol-3-one-20compounds or the 21-acyloxy derivatives thereof. It is to be understoodthatthe ester groups at C3 and C21 need not necessarilybe acetate butmay be any ester group capable of hydrolysis to a hydroxyl group.

What we claim as our inventionis;

1.- Process for preparing a AE-Zl-halo-ZO-keto pregnene which comprisesreacting a 17,21-di- 'hal'o-20Eketo pregnane with a dehydrohalogenatingagent of' the class consisting of tertiary amine bases and combinationsof an organic carboxylic acid and an alkali metal salt of "an organiccarboxylic acid.

2. Process for preparing a A -21-halo-20-keto pregnene which comprisesreacting a 17,21-dihalo-ZO-keto pregnane with the combination of anorganic carboxylic acid and an alkali metal salt of an organiccarboxylic acid.

3. Process for preparing a A -21-halo-pregnenol-3-one-20 which comprisesreacting a 17.21- dihalo-pregnanol-3- one-20 with the combination of anorganic carboxylic acid and an alkali metal salt of an organiccarboxylic acid.

4. Process for preparing a carboxylic acid ester of a -A-21-halo-pregnenol-3-one-20 which comprises reacting a carboxylic acidester of a 17,21-

dihalo-pregnanol-3-one-20 with the combination of an organic carboxylicacid and an alkali metal salt of an organic carboxylic acid.

5. Process fpr preparing A -21-bromo-pregnenol-3-fl-one-20 acetate whichcomprises reacting 17,21-dibromo-pregnanol-3-,3-one-20 acetate with thecombination of an organic carboxylic acid and an alkali metal salt of anorganic carboxylic acid.

6. Process for preparing steroid intermediate compounds which comprisesreacting a 17,21- dihalo-20-keto pregnane with the combination of anorganic carboxylic acid and an alkali metal salt of an organiccarboxylic acid thereby producing a A -21-halo-20-keto pregnene andreducing the latter to obtain a 21-halo-20-keto pregnane.

7. Process for preparing steroid intermediate compounds which comprisesreacting a 17,21- dihalo-ZO-keto pregnane with the combination of anorganic carboxylic acid and an alkali metal salt of an organiccarboxylic acid thereby producing a A -21-halo-20-keto pregnene andcatalytically hydrogenating the latter in the presence 'of a palladiumcatalyst to obtain a 21-halo-20- keto pregnane.

8. Process for preparing a steroid intermediate compound which comprisesreacting asteroidal compound having at ring D the formula;

CHzX (i=0 \M where X is a member of the class consisting of chlorine andbromine with the combination of an organic carboxylic acid and an alkalimetal 5 salt of an organic carboxylic acid thereby producing a steroidalcompound having in ring D the structur t 9. Process for preparing asteroid intermediate 1 compound which comprises reacting a steroidalcompound having at ring D the formula whereX is a member of the classconsisting of chlorine and brominewith'the combination of an organiccarboxylic acid and an alkali metal salt of an organic carboxylic acidthereby producing a steroidal compound having in ring D the structure 40crux and reducing the latter to obtain a steroid having in ring D thestructure 10. Process according to claim 9 in which the reduction iscatalyti hydrogenation in the presence of a palladium catalyst.

11. Process for preparing a steroid intermediate compound whichcomprises reacting the compound having the following structural formulawhere X is a member of the class consisting of' chlorine and bromine andR. is a member of the class consisting of '-OH and groups hydrolyzableto'--'-OHwith the combination of an organic carboxylic acid and analkali metal salt of an organic carboxylic acid thereby producing acompound having the following formula OH, CH. Eff i 12. Process forpreparing a steroid intermediate compound which comprises reacting thecompound having the following structural formula CHaX pound having thefollowing formula omx CH3 OH: I

- O=YO and reducing the latter compound to obtain a compound having thefollowing formula CHzX CH: CH: 6 O

13. Process according to claim 12 in which the reduction for catalytichydrogenation in the presence of a palladium catalyst.

14. Process for obtaining an intermediate for a compound having corticalhormone activity which comprises reacting a compound having the formulaOH. C 3

where X is a member of the class consisting of chlorine and bromine andR is a member of the CHzX CH: CH:-

Owes f reducing the latter to obtain a compound having the formula w 7'omX CH; OH: I

o=o t/\/W/ R\/\/ and exchanging an acyl oxy group of an organiccarboxylic acid for the halogen the last mentioned compound therebyproducing a compound having the formula I i so 7 OHIOACI i s j as 15.Process according to claim 14 in which the reduction is catalytichydrogenation in the presence of a palladium catalyst.

16. A steroidal compound having in ring D the following structure omx Uwhere X is a member of the class consisting of bromine-and chlorine. V

1'7. A steroidal compound having the formula CHaX CH: CH:

where X is a member of the class consisting of chlorine and bromine andR is a member of the class consisting of -OH and groups hydrolyzable toOH.

18. A carboxylic acid ester of a A -21-halopregnenol-3-one-20.

19. A 21 bromo-pregnenol-3-;3-one-20 acetate having a melting pointabout l-19l C,

20. 2l-bromo-A -pregneno1-3-p-one-20 having a melting point about -157"C.

RUSSELL EARL MARKER. HARRY M. CROOKS, JR.

